Categories: cell biology, immunology, physiology
BACKGROUND
Skin aging is a biological process characterized by architectural and functional alterations that promote reduced wound healing capacity and compromised protective role against external pathogens [1]. Many different types of cells compose the skin niche (Figure 1), which confers this tissue with a number of functions, including maintaining body temperature, gathering sensory information from the environment and as a protective barrier [2].
Figure 1: The human skin niche and the residing cell types. Dermis and epidermis are two of the main skin layers. On one hand, the dermis contains different immune cell types, as well as fibroblasts and endothelial cells. On the other hand, the epidermis contains melanocytes, keratinocytes at different differentiation states and Langerhans cells, a unique population of tissue-residing macrophages. From Nestle FO., et al., 2009.
Given the high complexity of the skin architecture, synergic malfunctioning of the different cell populations results in its age-associated frailty. Furthermore, chronic inflammation has been widely demonstrated to modulate a diversity of processes underlying aging in different tissues [3], including the skin. Nonetheless, there is lack of evidence on the types of skin immune cells responsible for the pro-inflammatory environment associated to aging, and on the identity of the inflammatory cytokines that play a role.
To address this knowledge gap and using transcriptomics at the single-cell level, Paloma Solá and colleagues decipher the major transcriptional changes of different cell populations residing in the skin that take place during aging and they identify one of the key players driving skin aging.
KEY FINDINGS
In this study, the authors performed single-cell RNA-sequencing (scRNA-seq) of the different skin cell populations from adult and aged mice (17 to 25-, and 80 to 90-weeks of age, respectively). For this, the authors combined dermis or epidermis cell isolation and sorting, with RNA extraction and sequencing. It is worth noting that this process was performed in the dark period, to coincide with the active phases of mice.
By using this approach, transcription profiles linked to defective functions and increased inflammation were observed in both non-immune and immune dermal cells of aged mice. Among the former, Schwann cells appeared to be less efficient in their regenerative functions in skin, whereas endothelial cells and fibroblasts showed a shift towards a more pro-inflammatory state. Among the latter, dermal myeloid cells, T cells and innate lymphoid cells (ILCs) presented a remarkable upregulation of genes involved in different pro-inflammatory signaling pathways. Importantly, the authors noticed that in the case of specific T cell subsets and ILCs, these genes were predominantly related to the pro-inflammatory cytokine interleukin 17 (IL-17).
To address the physiological contribution of IL-17 signaling to skin aging, the authors treated aged mice (73-weeks-old) with IL-17 neutralizing antibodies for 12 weeks. They then assessed the transcriptomics of skin cells at single-cell level, as well as physiological parameters, such as the thickness of the cornified layer and the whole epidermal layer, as well as hair growth. First, the authors observed that IL-17 neutralization ameliorated the pro-inflammatory transcriptional state of dermal cells. Strikingly, the predominant anti-inflammatory effects were observed in non-immune dermal cells (fibroblasts, endothelial cells and Schwann cells). This is an interesting observation, since it suggests that non-immune dermal cells are most sensitive to anti-inflammatory treatments. Furthermore, assessment of the transcriptomics of epidermal cells upon IL-17 blockade also showed a restoration in the expression levels of pro-inflammatory cytokines. Importantly, reduction of other known epidermal aging traits was also observed, including pathways involved in oxidative stress functions and wound healing, highlighting the relevance of IL-17 in the development of age-associated traits in the skin. Lastly, aged mice treated with IL-17 neutralizing antibodies exhibited increased epidermal thickness and decreased cornified layer thickness compared to their adult counterparts, along with an improvement of the capacity of hair follicle growth upon epilation. This suggests that IL-17 blockade in aged mice improves epidermal health, thus pinpointing the physiological relevance of IL-17 skin aging.
WHY I CHOSE THIS PREPRINT
In their preprint, Paloma Solá and colleagues provide a very comprehensive and detailed characterization on the types of skin cell populations that present altered transcriptomics associated to aging. Besides, their approach allowed them to identify that upregulated IL-17 in specific lymphoid cell subsets acts as the driver of the pro-inflammatory state associated to skin aging. In my opinion, the authors elegantly provide valuable and complex data in a very easy-to-follow manner, making evident the real impact of their study. In fact, Paloma Solá and colleagues not only reveal a potential treatment to prevent unhealthy skin aging, but they also open the possibility to identify the exact molecular pathways that promote physiological skin aging.
MY QUESTIONS TO THE AUTHORS
- According to your data, there is a number of pro-inflammatory cytokines that show upregulated expression levels in different skin cell types of aged mice, including IL-6, IL-2, NFkB, and the STAT or TNF signaling pathways. Why did you focus on IL-17 signaling?
- If you performed a proof-of-concept experiment by providing adult mice with IL-17 in their skin, would you expect them to show accelerated skin aging?
- Considering your data on the anti-inflammatory effect that IL-17 blockade exerts in the skin niche, what is your speculation on the triggers of IL-17 upregulation in immune skin cells of aged mice?
- Does the IL-17 signaling from immune skin cells become systemic during aging? Could it be that IL-17 from other inflamed tissues is promoting its own regulation in the skin niche?
- Could enhanced IL-17 signaling be considered as a hallmark of autoimmune diseases?
REFERENCES
[1] López-Otín C., et al., The Hallmarks of Aging. Cell, 2013. doi: 10.1016/j.cell.2013.05.039
[2] Nestle FO., et al., Skin immune sentinels in health and disease. Nat Rev Immunol, 2009. doi: 10.1038/nri2622
[3] Ferrucci L and Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol, 2018. doi: 10.1038/s41569-018-0064-2
doi: https://doi.org/10.1242/prelights.31511
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